Solid-pseudopapillary neoplasms (SPNs) are rare human pancreatic neoplasms usually associated with a good prognosis. In contrast to other pancreatic tumours, aberrant activation of the Wnt–β-catenin pathway appears to be a constant feature in SPN. Aside from activation of the Wnt–β-catenin pathway, little is known about biological pathways deregulated in SPN. We carried out transcriptome profiling of SPN to gain insights into the pathogenesis of these tumours. As expected, the over-expression of AXIN2, TBX3, SP5 and NOTUM demonstrated activation of the β-catenin pathway. Members of the Notch pathway (HEY1, HEY2, NOTCH2) were also up-regulated, relative to their expression in ductal adenocarcinomas (DAC) or pancreatic endocrine tumours (PET). Other genes, such as EDN3, HAND2, netrin-G2 and the receptor netrin-G1 ligand, involved in neural crest differentiation, were also identified as altered. Increased levels of SOX10 and TuJ-1 proteins were also indicative of neural-like differentiation. In conclusion, SPN display a complex expression profile, distinct from that observed in PET and DAC and involving both the β-catenin and Notch pathways, together with expression of neural differentiation markers. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.